RESUMEN
Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature.
Asunto(s)
Deformidades Congénitas de las Extremidades/genética , Mutación , Proteína Relacionada con la Hormona Paratiroidea/genética , Animales , Células Cultivadas , Embrión de Pollo , Codón sin Sentido , Modelos Animales de Enfermedad , Femenino , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/patología , Genes Dominantes , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Humanos , Deformidades Congénitas de las Extremidades/patología , Masculino , Ratones , Ratones Noqueados , Mutación Missense , Proteína Relacionada con la Hormona Paratiroidea/deficiencia , Linaje , Fenotipo , Mutación Puntual , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Eliminación de SecuenciaRESUMEN
INTRODUCTION: The clinical phenotype of the chromosome 2q31 deletion syndrome consists of limb anomalies ranging from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. Additional internal organ anomalies-for example, heart defects, ocular anomalies-may be present. Hemizygosity for HOXD13 and EVX2 genes was thought to cause the observed skeletal defects. Recently, based on the phenotype of patients with overlapping 2q31 interstitial deletions, a new SHFM5 locus was proposed, proximal to the HOXD cluster, between EVX2 and marker D2S294. DLX1 and DLX2 haploinsufficiency was suggested as the most plausible explanation for the observed SHFM-like limb anomalies in these cases. METHODS AND RESULTS: Five unique, interstitial 2q31 deletion patients were selected to further characterise the 2q31 region and to establish a genotype/phenotype correlation map. The size of the deletions was delineated with a chromosome 2 specific tiling path bacterial artificial chromosome (BAC) array. The clinical and molecular data for this group of patients were compared to others in the literature. A common locus for the observed skeletal anomalies, including the HOXD genes and surrounding regulatory sequences, was delineated. These results correlate with recently published studies in animal models. In addition, a critical region for the facial gestalt of the 2q31.1 microdeletion syndrome was delineated. CONCLUSIONS: These results reinforce the hypothesis that the variable skeletal phenotype in 2q31 deletion patients is a result of hemizygosity for the HOXD genes and that the 2q31.1 microdeletion syndrome is a well defined and clinically recognisable phenotype.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 2/genética , Deformidades Congénitas de las Extremidades/genética , Fenotipo , Anomalías Múltiples/patología , Trastornos de los Cromosomas/patología , Cromosomas Artificiales Bacterianos , Hibridación Genómica Comparativa , Femenino , Hemicigoto , Proteínas de Homeodominio/genética , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Deformidades Congénitas de las Extremidades/patología , Masculino , Síndrome , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: To report the phenotype-genotype correlation in a Belgian family that was ascertained to have a novel missense mutation in the NOG gene mapping to chromosome 17q22. STUDY DESIGN: To describe the phenotype, a retrospective case study was performed based on the otologic, audiologic, ophthalmologic, and radiologic data of the mutation carriers of the NOG gene. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carried the novel missense mutation in the NOG gene (NOG, Trp205Cys [W205C]; 1426G>C). INTERVENTIONS: Diagnostic otologic and ophthalmologic examination, audiometric analysis, and radiologic imaging. MAIN OUTCOME MEASURES: Phenotype-genotype correlations. RESULTS: All five mutation carriers had a typical facies. Bilateral proximal symphalangism and hyperopia were present in 80%. Five of 10 ears also had progressive early-onset conductive hearing loss caused by stapes ankylosis. CONCLUSIONS: So far, 14 independent NOG mutations have been identified. The autosomal dominant disorder described in the present family was caused by a novel NOG missense mutation (NOG, Trp205Cys [W205C]; 1426G>C). The phenotype correlated well with the facioaudiosymphalangism syndrome. The mutation carriers demonstrated progressive multiple joint fusions, hyperopia, early-onset conductive deafness, and a typical facies.